Structural and Functional Studies of Iron Transport and Homeostasis

铁转运和稳态的结构和功能研究

• 批准号: 8312564
• 负责人: CHARLES MARTIN LAWRENCE
• 金额: $ 24.27万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312564
• 关键词: Anemia; Binding; Biochemical; Cirrhosis; Defect; Diabetes Mellitus; Disease; Face; Family; Fluorescence; Goals; Grant; Health; Heme; Hereditary hemochromatosis; Homeostasis; Human; In Transferrin; Intervention; Investigation; Iron; Iron Overload; Malignant neoplasm of liver; Membrane; Metabolism; Mutagenesis; Neurodegenerative Disorders; Oxidoreductase; Pharmacotherapy; Population; Predisposition; Primary carcinoma of the liver cells; Proteins; Stroke; Structure; Structure-Activity Relationship; Transmembrane Domain; extracellular; genetic variant; glycosylation; insight; iron (III) reductase; iron deficiency; mortality; mutant; oxidation; structural biology; therapy development; uptake

DESCRIPTION (provided by applicant): Diseases of iron transport and metabolism are among the most prevalent causes of human suffering and mortality. Greater than one billion people throughout the world are iron deficient and genetic variants conferring susceptibility to iron overload (hereditary hemochromatosis) are highly prevalent in some populations. As a necessary step in the development of treatments for iron deficiency and iron overload, our long-term goals are to achieve greater biochemical and structural understanding of iron transport and homeostasis. The transport of iron across membranes is substantially dependent upon protein reductases that convert or maintain iron in the correct oxidation state for transport. Ferric reductases and mechanisms of iron reduction are thus worthy of significant investigation as they may provide targets for pharmacological intervention to either promote or inhibit cellular iron uptake. We propose a combination of functional and structural studies on the Steap family of metalloreductases, which have been recently implicated in iron transport and homeostasis. These studies will provide insight into the mechanism of iron uptake in the transferrin-cycle, and appear relevant to the mechanisms of non-transferrin bound iron uptake as well. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant will investigate the structural biology of iron transport and homeostasis, with an emphasis on the Steap family of metalloreductases. Defects in iron homeostasis leading to insufficient or excess iron are relevant to a slew of disease states, including cirrhosis of the liver, cancer in general and hepatocellular carcinoma in particular, diabetes, anemia and iron overload, stroke and various neurodegenerative diseases. For this reason, the Steap proteins represent potential targets of drug therapy in a variety of human disorders.

描述（由申请人提供）：铁运输和代谢的疾病是人类痛苦和死亡率最普遍的原因之一。全世界有超过10亿人是铁缺乏的，遗传变异赋予铁超负荷敏感性（遗传性血色素沉着症）在某些人群中非常普遍。作为开发铁缺乏症和铁超载治疗方法的必要步骤，我们的长期目标是实现对铁运输和稳态的更深入的生化和结构理解。铁跨膜的运输基本上取决于在正确的氧化状态下转化或维持铁的蛋白质还原酶以进行运输。因此，铁还原酶和还原的机制值得进行大量研究，因为它们可能为促进或抑制细胞铁吸收的药理干预提供靶标。我们提出了关于金属酶酶家族的功能和结构研究的结合，最近与铁运输和稳态有关。这些研究将洞悉转铁蛋白周期中铁的摄取机理，并似乎与非转铁蛋白结合的铁摄取的机理有关。公共卫生相关性：本赠款中提出的研究将调查铁运输和稳态的结构生物学，重点是金属果酶的STEAP家族。铁稳态的缺陷导致不足或过量铁与多种疾病状态有关，包括肝脏，癌症，尤其是癌症，尤其是肝细胞癌，糖尿病，贫血，贫血和铁超负荷，打roke，卒中和各种神经退行性疾病。因此，STEAP蛋白代表了多种人类疾病中药物治疗的潜在靶标。